The plant Aglaia native of the tropical rain forests of Indonesia and Malaysia is the source of a unique group of densely functionalized natural products some of which are presented on FIG. 1 (P. Proksch et al., Curr. Org. Chem., 2001, 5: 923-938). The rocaglamides, including the parent molecule (compound A; M. L. King et al., J. Chem. Soc., Chem. Commun., 1982, 1150-1151) and the recently isolated dioxanyloxy-modified derivative silvestrol (compound B; B. Y. Hwang et al., J. Org. Chem., 2004, 69: 3350-3358), possess a cyclopenta[b]tetrahydrobenzofuran ring system (presented in red on FIG. 1). The structurally related aglains (e.g., compounds C and D), which contain a cyclopenta[bc]benzopyran structure (presented in blue on FIG. 1), have also been isolated from Aglaia (V. Dumontet et al., Tetrahedron, 1996, 52: 6931-6942). The forbaglins (e.g., compound E) are benzo[b]oxepines (in green on FIG. 1) derived from formal oxidative cleavage of the aglain core.
The rocaglamides have been shown to exhibit potent anticancer (M. L. King et al., J. Chem. Soc., Chem. Commun., 1982, 1150-1151) and antileukemic activity (S. K. Lee et al., Chem. Biol. Interact., 1998, 115: 215-228) as well as NF-κB inhibitory activity at nanomolar concentrations in human T cells (13. Baumann et al., J. Biol. Chem., 2002, 277: 44791-44800). The rocaglate silvestrol B displays cytotoxic activity against human cancer cells comparable to the anticancer drug TAXOL® (B. Y. Hwang et al., J. Org. Chem., 2004, 69: 3350-3358).
As proposed by Proksch (P. Proksch et al., Curr. Org. Chem., 2001, 5: 923-938) and Bacher (M. Bacher et al., Phytochemistry, 1999, 52: 253-263), and as shown on FIG. 2, the rocaglamides may be biosynthetically derived from reaction of trimethoxy-substituted 3-hydroxyflavone with cinnamide derivatives to afford the aglain core, followed by skeletal rearrangement.
The rocaglamides have been the subject of a number of synthetic investigations (see, for example, G. A. Kraus and J. O, Sy, J. Org. Chem., 1989, 54: 77-83; B. Trost et al., J. Am. Chem. Soc., 1990, 112: 9022-9024), including a biomimetic approach involving a [2+2] photocycloaddition (H. C. Hailes et al., Tetrahedron Lett., 1993, 34: 5313-5316). However, syntheses of the related aglain (V. Dumontet et al., Tetrahedron, 1996, 52: 6931-6942), aglaforbesin (V. Dumontet et al., Tetrahedron, 1996, 52: 6931-6942), or forbaglins have not been reported. A unified synthetic approach to these molecules based on biosynthetic still remains to be developed.
The present Applicants have recently reported (B. Gerard et al., J. Am. Chem. Soc., 2004, 126: 13620-13621; and International Application WO 2005/092876) the synthesis of rocaglamide natural products via [3+2] dipolar cycloaddition of an oxidopyrylium species derived from excited state intramolecular proton transfer (a general synthetic scheme is presented on FIG. 3).